Joe Cornicelli

The Pathway to Improved Translation with Targeted In Vivo Modeling

The tools of genetic engineering present us with unique opportunities to make animal model systems more predictive of target engagement, human efficacy, and safety

Translational research within the pharmaceutical and biotech industries is becoming less efficient despite the emergence of significant technologies designed to facilitate that process. The number of FDA-approved drugs per billion R&D dollars spent has halved about every 9 years since 1950. This poses two questions: Where, in the process, are we failing, and Why are we failing? Most clinical trials in Phase II/III fail because of lack of efficacy (52%) or safety (24%). Those failures are related, in large part, to the inability to base those trials on valid translational models.

We rely extensively on animal models to drive clinical development plans, yet the truth is that most animal models rarely faithfully recapitulate the human diseases they are intended to mimic. That is not to say that they are useless, but that they need to be applied judiciously with respect to the pathways and mechanisms that drive the human pathophysiology. Fortunately, the tools of genetic engineering present us with unique opportunities to improve animal model systems to become more predictive of target engagement, human efficacy, and safety.

CRISPR and animal model creation

The gene editing technology known as CRISPR/Cas9 has revolutionized our ability to make specific modifications to the genome. Of importance here is that this system is proving to be the most efficient approach for editing the rat genome providing investigators with model systems that are a bit more like human physiology in many areas. Application of CRISPR technology also provides a path for rapid generation of structural variants with deletions, duplications, and inversions of relatively large genomic regions in founder animals. This same technology can efficiently create single nucleotide polymorphisms (SNPs) which are the most abundant source of genetic variation in the human genome. It has also been used in mouse models for humanizing large regions of DNA.

But as the saying goes, just because you can do something doesn’t mean you should do it. What then is the evidence that engineered animal models are more translatable to humans with respect to drug discovery and development? Predicting efficacy of drugs designed to reduce the morbidity and mortality of cardiovascular disease is of paramount importance for proceeding with clinical trials that are likely to be long and expensive. Generating data in a reliable animal model provides confidence in both the mechanism and safety of a given approach.

ApoE knockout mouse

Consider the apolipoprotein E (Apo E) knockout mouse generated by two independent laboratories in 1992. Apo E is responsible for clearing dietary and endogenous lipid, and in the removal of cholesterol from peripheral tissues. The absence of Apo E creates very robust atherosclerosis in these animals.

The Apo E deficient mouse was used to demonstrate that inhibiting cholesterol absorption would reduce both plasma cholesterol and the development of atherosclerosis, providing confidence to proceed with clinical trials for ezetimibe. That drug was approved in 2002 for the treatment of hypercholesterolemia. Subsequent clinical trials demonstrate that ezetimibe significantly reduced major cardiovascular events in high-risk patients with pre-existing cardiovascular disease.

Recent advances in genetic engineering, such as CRISPR, are only making more precise modifications in the rat and mouse genome. The advances in technology bring with them great responsibility. How then do we apply these advances to translational research? The challenges we face center on their judicious use to improve translatability for the eagerly waiting patient population. It is incumbent upon us a scientists and investigators to take full advantage of this opportunity to drive the search for better, more effective therapies and to reduce failures in the clinic.

Register for this webinar on Sept. 16 where Joe Cornicelli, PhD, will discuss the pathway to improved translation with targeted in vivo modeling.